Myeloproliferative neoplasms (MPN) are a class of hematologic makignancies arising from haematopoietic progenitors, and include diseases such as chronic myeloid leukemia (CML), polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF). In 2005, a recurrent somatic point mutation in the pseudokinase domain of the Janus kinase 2 (JAK2) gene was discovered to be present in a large proportion of patients suffering from these diseases (see, e.g., Levine, R. et al. 2005, Cancer Cell 7:387; James, C. et al. 2005, Nature 434:1144). Specifically, in patients with PV, ET, and PMF the activating JAK2V617F mutation occurs with a frequency of between 81-99%, 41-72% and 39-57% respectively (see, e.g., Levine, R. L. et al. 2007, Nat. Rev. Cancer 7:673). Additionally, over-activation of JAK/STAT signaling has been described in a subset of patients that do not harbor JAK mutations (see, e.g., Quintas-Cardanam A. et al. 2013, Clinical Cancer Res. Doi:10.1158/1078-0432.CCR-12-0284). Taken together, evidence to date supports the targeting of the JAK/STAT pathway, specifically JAK2, in patients with various MPNs.
Recently, clinical trials have been carried out to evaluate the efficacy of the second generation JAK1 and JAK2 inhibitor ICNB018424 in patients suffering from MPNs. The conclusions of these trials show that, while transiently effective at reducing spleen size and alleviating some symptoms (in about 50% of patients), INCB018424-resistance is a real problem facing the drug moving forward in the clinic. A significant fraction of patients will experience suboptimal responses, and a few, if any, will see a substantial reduction in JAK2V617F allele burden (see, e.g., Verstovsek, S. et al. 2012, N. Eng. J. Med. 366:799; Tefferi, A. et al., 2012, N. Eng. J. Med. 366:844; and Tefferi, A. et al., 2012, Blood 119:2721). Treatment failures seen in the clinic could be due to: (1) second site mutations in the kinase domain (see, e.g., Deshpande, A. et al. 2011, Leukemia 26:708); (2) heterodimerization of activated JAK2 and JAK1 or TYK2, leading to reactivation of signaling to downstream STAT proteins (see, e.g., Koppikar, P. et al. 2012, Nature 489:155); (3) previously uncharacterized downstream or parallel pathway activation (see, e.g., Poulikakos, P. I. et al. 2011, Cancer Cell 19:11); or (4) some combination of these three.
In light of the development of JAK2 inhibitor resistance in the treatment of some cancers, there is a need to understand and develop effective therapies for the treatment of cancers having developed resistance to JAK2 inhibitors.